tbuckley/cabot-search huggingface dataset:
CNSC-38. EGFR AMPLIFICATION IS A PUTATIVE RESISTANCE MECHANISM FOR NSCLC-LM PATIENTS WITH TKI THERAPY AND IS ASSOCIATED WITH POOR OUTCOME
Authors: Hainan Yang, Lei Wen, Caicun Zhou
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Leptomeningeal metastases (LM) have become increasingly common in NSCLC patients who harbor epidermal growth factor receptor (EGFR) mutation treated with EGFR-TKI and are correlated with inferior prognosis. Evidence in prior research demonstrated that EGFR amplification was more likely presented in advanced clinical stages and was associated with worse survival. However, whether the EGFR amplification is a prognostic marker in NSCLC-LM is still inconclusive. METHODS This study enrolled patients diagnosed with NSCLC-LM from June 2019 to September 2021, who had received previous EGFR-TKI at Guangdong Sanjiu Brain Hospital. Cerebrospinal fluid (CSF) samples were collected and subjected to targeted next-generation sequencing (NGS) of 168 cancer-related genes. Clinical characteristics and overall survival (OS) were compared in patients with and without EGFR amplification. RESULTS This study enrolled 53 NSCLC-LM patients, all of whom had EGFR mutations. TP53 and EGFR amplification are the two most frequent mutations in the study cohort, presenting 72% (38 of 53) and 40% (21 of 53), respectively. The rate of EGFR amplification was much higher at the time of leptomeningeal progression than at initial diagnosis (p&amp;lt; 0.01). Karnoskfy performance status was poorer (p=0.021), and CSF pressure was higher (p=0.0067) in patients with than without EGFR amplification. A multivariable Cox proportional hazard regression model showed that EGFR amplification was an independent prognostic factor for poorer OS (8.3 vs 15 months; p=0.017). Median OS was shorter in NSCLC-LM patients with mutated than wild-type TP53, but the differences was not statistically significant (10 vs 17.3 months, p=0.184). CONCLUSIONS EGFR gene amplification could be a potential resistance mechanism to EGFR-TKI failure in NSCLC-LM and is associated with inferior clinical outcomes.
EPID-23. TRAUMATIC BRAIN INJURY AND SUBSEQUENT BRAIN TUMOR DEVELOPMENT: A SYSTEMATIC REVIEW OF THE LITERATURE
Authors: Darsh Shah, Akshat Sanan, Alexis Morell, Daniel Eichberg, Ashish Shah, Evan Luther, Turki Elarjani, Dominique Higgins, Nitesh Patel, Jonathan Jagid, Michael Ivan, Ricardo Komotar
Journal: Neuro-Oncology (2022)

Abstract Background The role of prior head trauma in stimulating brain tumor development has been previously described in the literature but continues to be debated. The goal of this study was to conduct a systematic review interrogating the contemporary literature to delineate any possible relationship between traumatic brain injury and brain tumor development. Methods A systematic review exploring development of post-TBI brain tumor was conducted by searching electronic databases. Abstracts from articles were read and selected for full-text review according to criteria previously established in the scientific literature. Relevant full-text articles were divided into case reports and single-arm studies and epidemiological studies. Results Of 1070 resultant articles, 18 case reports and single-arm studies (level of evidence of IV and V) with 45 patients were included. The most common cause of TBI was traffic accidents. The average period between TBI and subsequent tumor diagnosis was 12.8 years. Meningiomas represented the largest share of tumors, followed by gliomas. Most post-TBI brain tumors developed in the frontal and temporal lobes. Fifteen epidemiological studies were also interrogated from a variety of countries (level of evidence of III). Case–control studies were more common than cohort studies. There were 9 of 15 studies proposed a possible relationship between history of head trauma and development of brain tumor. Conclusion The relationship between head trauma and neoplastic growth continues to be heavily debated. There are certainly case reports and epidemiological studies in the literature that suggest a correlational relationship between the two. However, there is no concrete evidence of a causal relationship between TBI and brain tumors. More research is needed to definitively delineate the extent of any such relationship.
BIOM-24. TARGETED NEXT-GENERATION SEQUENCING (NGS) OF TEMPORALLY MATCHED CEREBROSPINAL FLUID (CSF) AND TUMOR TISSUE IN PATIENTS WITH RECURRENT GLIOBLASTOMA (GBM)
Authors: Aseel Abdalla, Jacob Till, Stephanie Yee, Donald O'Rourke, Steven Brem, Nduka Amankulor, Isaac Chen, Zev A Binder, Arati Desai, Richard Phillips, Jasmin Hussain, Yolanda Kry, Michael Caldwell, Nike Beaubier, Stephen Bagley, Erica L Carpenter
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND GBM genomic profiling relies on sequencing a limited tumor tissue sample, which is invasive and may underrepresent molecular heterogeneity. CSF, which can be obtained less invasively, is in intimate contact with tumor lesions and may better capture the full genomic profile of the tumor. However, datasets with contemporaneously collected CSF and tissue to support this claim have been lacking. To evaluate the performance of CSF NGS, we conducted a pilot study in patients with GBM undergoing a resection for suspected recurrence following first-line chemoradiotherapy. METHODS Paired CSF and tissue samples were sequenced using a hybrid capture-based NGS assay. Clinically meaningful variants were defined as those that are potentially targetable using off-label or clinical trial options, exhibit prognostic value, or may predict response or resistance to specific treatments. RESULTS Eighteen patients were enrolled, and 13 of 18 CSF samples (72.2%) were sequenced successfully. At least one variant was detected in all CSF samples analyzed. A median of 7 variants (range 1—67) was detected per sample across 54 genes. The median variant allele fraction was 0.6% (range 0.2—72.4%). Among 38 clinically meaningful genes, 102 variants were detected; 25 (24.5%) were detected in both tissue and CSF, while 60 (58.8%) were detectable solely in CSF. Hypermutation was detected by CSF in one patient. Of the 82 variants detected in this patient’s tumor, 15 (18.3%) were identified in both tissue and CSF, 15 (18.3%) were identified only in the tissue, and 52 (63.2%) were identified only in the CSF. CONCLUSIONS CSF NGS detects clinically meaningful variants at a substantial rate and frequently identifies mutations not detected by matched tissue NGS. These results suggest that CSF may be a suitable source material for tumor profiling, overcoming the limitations of tissue, and may also provide a more comprehensive tumor profile.
MODL-41. ORGANOTYPIC BRAIN SLICE CULTURE PLATFORM AS A NOVEL PRE-CLINICAL MODEL FOR PATIENT DERIVED CELL LINES
Authors: Breanna Mann, Xiaopei Zhang, Noah Bell, Adebimpe Adefolaju, Rajaneekar Dasari, Shawn Hingtgen, Andrew Satterlee
Journal: Neuro-Oncology (2022)

Abstract The lack of experimentally tractable models that recapitulate brain structure and function represents a major impediment in the development of novel treatment options for brain cancer. In vitro assays, though fast and high throughput, produce artificial results which do not fully encompass the clinically relevant outcome. Low passage patient derived cell lines offer an advantage over immortalized cell lines in terms of relation to the clinical presentation. Low passage patient derived cell lines, however, show slower growth and decreased tumorgenicity. We have previously shown that the use of organotypic brain slice culture (OBSCs) can recapitulate growth patterns and migration which is seen in vivo. We have further expanded the OBSCs to study their use as a model for patient derived cell lines. Some cell lines such as MS21, a human glioblastoma, or IFF109-DMG, a human pediatric diffuse midline glioma, are simply supported over a four-day time period, whereas other lines such as IFF105-DIPG, a pediatric human diffuse intrinsic pontine glioma, can grow over 3-fold in a 4-day time period. Additionally, we can assess treatment response to a variety of clinically relevant chemotherapeutics. The decreased variability with the OBSCs allows for the assessment of minute differences in treatment response. Overall, these results suggest the OBSC with patient derived cell lines have the potential to be effective models to accelerate preclinical evaluation of therapeutics and guide drug development towards more effective treatment strategies.
TMIC-03. TUMOR INFILTRATING LYMPHOCYTES IN BRAIN METASTASIS: CLINICOPATHOLOGICAL EVALUATION AND COMPARISON WITH PAIRED PRIMARY
Authors: Ayushi Sahay, Mayur Indave, Abhishek Chatterjee, Aliasgar Moiyadi, Vijay Patil, Tejpal Gupta, Prakash Shetty, Vikas Singh, Nandini Menon, Arpita Sahu, Amit Chaudhari, Epari Sridhar
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION Little is known about tumour-infiltrating lymphocytes (TILs) in brain metastasis (BM) and their utility as predictive biomarker for immunotherapy. AIM: To analyze TILs in BM, and correlate with corresponding paired primary (PP). METHODS Inclusion: Histologically confirmed BM and PP (2015-2020). Exclusion: Hematological malignancies, spinal cord/meningeal metastasis, pediatric age, slides/blocks not available. Final Nf 277 BM; 64 PP. One H&amp;E slide from both PP &amp;BM assessed for stromal TILs (sTILs) and intratumoral TILs (iTILs) as per International TIL Working Group guidelines. RESULTS Median sTILs (10%) were significantly higher than iTILs (1%) in primary and BM (p-value &amp;lt; 0.001). sTILs were mild (&amp;lt;10%) in majority of primary (57.8%) and BM (59.9%), while iTILs were nearly always mild (primary 97.1%; BM 96.9%). Between PP and BM, no change in sTIL category in 48.43%, while conversion in 51.56%, with higher to lower conversion (66.67%) &amp;gt; lower to higher (33.33%). Conversion rate higher for breast (54.3%) &amp;GIT (62.5%) than lung (45.5%) &amp;GUT (40%). In BM, preoperative steroid therapy (PST) showed lower sTILs (≤10%) (p-value= 0.041), and adenocarcinoma histology higher sTILs ( &amp;gt;10%) (p-value= 0.001), while precocious metastasis (p-value= 0.051) and absence of extracranial metastasis (p-value= 0.083) trended towards higher sTILs. Median survival of whole cohort was 20 months (95% CI 14.4-25.68 months). Presence of extracranial metastasis (p-value= 0.01); precocious BM (p-value= 0.007) showed lower overall survival (OS), while adenocarcinoma histology better OS (p-value= 0.029), in both univariate and multivariate analysis. Absence of PST showed longer median survival, though not significant (24.1 vs 19.8months; p-value= 0.19). CONCLUSIONS sTILs predominantly show high &amp;gt;low conversion between PP and BM, signifying lowered immune response in BM. Thus, evaluation of sTILs in BM, wherever tissue available, may be indicated if immunotherapy is considered. Parameters with higher sTILs showed longer survival, possibly indicating prognostic role of tumor microenvironment in BM.
SURG-16. THALAMIC GLIOMAS AND THEIR SURGICAL STRATEGY: A SYSTEMATIC REVIEW
Authors: Adam Levy, Tiffany Eatz, Alexis Morell, Martin Merenzon, Dominique Higgins, Manuela Guyot, Nitesh Patel, Daniel Eichberg, Michael Kader, Evan Luther, Ricardo Komotar, Michael Ivan
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION Until recent decades, thalamic gliomas had been considered largely inoperable. These lesions are deep-seated and surrounded by vital structures. However, as technology and imaging modalities have improved, so have treatment modalities. Currently, a range of surgical approaches are used, partially dependent on the location of the lesion; although no consensus has been reached regarding optimal surgical management. OBJECTIVE To conduct a systematic review of the literature to describe the current surgical outcomes of adult thalamic gliomas. METHODS Four databases were searched with keywords “‘thalamic glioma’ AND ‘surgical intervention’ OR ‘thalamic glioma’ AND ‘surgical treatment’” for articles assessing surgical techniques of adult thalamic glioma resection. Our systematic review was reported in accordance with the PRISMA guidelines. 793 full-text studies were assessed for eligibility. Ultimately, 14 studies were included. RESULTS The mean age was of 33.57 years (18-83). In 479/507 cases the surgical strategy used was described. The transcortical approach was the most utilized (37.8% of cases). The remaining cases employed transventricular (23.8%), transcallosal (22.8%), and trans-sylvian transinsular (2.92%) approaches, among others. Gross total resection (GTR), subtotal resection (STR), and partial resection were achieved in 36.7%, 47.4%, and 15.9%, respectively. New temporary postoperative deficits were observed in 57/507 patients and new permanent deficits in 56/507 patients. There were 18 total perioperative deaths reported. The degree of morbidity across approaches was recorded in just one study, where no significant difference was found. The mean overall survival of adult patients after surgery ranged from 11.5 to 27.39 months across studies. CONCLUSION There is a lack of statistically strong data that addresses which surgical approach causes less morbidity and allows a better surgical resection for thalamic gliomas. Ultimately, surgical resection of adult thalamic gliomas can increase overall survival but at the risk of operative morbidity. Transcortical approaches appear to carry a greater overall survival
MODL-01. TRACTABLE PATIENT-DERIVED MODELS FOR PRECLINICAL THERAPEUTIC STUDIES OF CNS METASTASES
Authors: Morana Vojnic, Igor Odintsov, Michael D Offin, Allan J W Lui, Inna Khodos, Qing Chang, Marissa S Mattar, Elisa De Stanchina, Marc Ladanyi, Romel Somwar
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION Brain metastases are the most common brain tumors and occur in 10-30% of cancer patients, whereas leptomeningeal disease (LMD) occurs in approximately 5% of adults with systemic malignancies. Tractable preclinical disease models that faithfully represent metastasis to the brain and recapitulate LMD are needed to improve our understanding of the biological basis of CNS disease as well developing effective therapeutic strategies. Our goal in this study was to generate representative preclinical disease models using two methods. METHODS We isolated tumor cells from CSF of 16 patients with cytologically proven LMD (9 NSCLC, 1 melanoma, 1 ovarian cancer, 1 endometrial cancer, and 4 breast cancer) and implanted the cells subcutaneously into the flank of immunocompromised mice. Cell lines were also generated from PDX tissues. Models were characterized by next-generation sequencing (NGS). We also generated a model of CNS metastasis of kinase-driven sarcoma by intracardiac (IC) injection of human mesenchymal stem cells (HMSC) expressing a SPECC1L::RET fusion (CRISPR-Cas9 gene editing). The cells (HMSC-RET) were also labeled with a luciferase construct to allow non-invasive bioluminescence imaging. RESULTS We established three PDX models (2 lung, 1 ovarian) from CSF (19% success rate compared to approximately 33% for solid tumors) and matched cell lines from the resulting PDX tissues. Intracardiac injection of HMSC-RET cells resulted in tumors establishing in several peripheral organs and the brain. SUMMARY AND CONCLUSIONS We have established disease models of CNS metastasis and LMD. Translational studies where patients with clinical suspicion of LMD undergo CSF sampling, NGS/ctDNA analysis, and PDX modeling are crucial in improving our understanding of this metastatic compartment and investigating novel treatment paradigms. Future studies will be focused on examining the biochemical and genetic nature of these tumors as well as developing effective therapeutic strategies.
TMIC-58. PATTERNS OF CELLULAR SUBPOPULATION COHABITATION DEFINE GLIOBLASTOMA STATES
Authors: Kamila Bond, Lee Curtin, Andrea Hawkins-Daarud, Javier Urcuyo, Gustavo De Leon, Christopher Sereduk, Kyle Singleton, Jazlynn Langworthy, Pamela Jackson, Chandan Krishna, Richard Zimmerman, Devi Patra, Bernard Bendok, Kris Smith, Peter Nakaji, Kliment Donev, Leslie Baxter, Maciej Mrugala, Osama Al-Dalahmah, Leland Hu, Nhan Tran, Joshua Rubin, Peter Canoll, Kristin Swanson
Journal: Neuro-Oncology (2022)

Abstract Characterizing intra- and inter-tumoral heterogeneity of glioblastoma has historically relied on discrete classifications of malignant cell populations leaving immune and other cell populations, known to exist admixed with the malignant tumor cells, relatively neglected. Manifold learning algorithms can manage deconvolving multiple cell populations and are often used to track cell state transitions in single cell transcriptomics. We applied a manifold learning approach to TCGA microarray data (Nf525) and bulk transcriptomics of 134 image localized biopsies across 30 patients with primary and 9 with recurrent glioblastoma to further elucidate how to organize biopsies across a spectrum of possible tissue states. The algorithm revealed a low-dimensional manifold graph for which each biopsy lives across 3 polarizing tissue states - one that is associated with diffusely invaded brain, one that is enriched in mesenchymal genes, and one that is enriched in classical proliferative tumor signatures. We deconvolved the bulk transcriptomics of the image-localized biopsies to reveal the relative abundance of 18 malignant, immune, and other cell subpopulations in each biopsy. Overlaying the cellular decomposition onto the manifold graph visualizing the tissue state distributions revealed that transitions between states correlate with changes in cellular cohabitation composition. The tumor cellular cohabitation ecologies have the lowest diversity, as inferred by ecological measures such as Shannon entropy and evenness, at the distal poles of the graph when compared to the transitional arms. Further, we found that the relationship between imaging appearance of contrast enhancement on T1-weighted MRI and the biopsy cellular composition varies with sex and primary vs recurrent biopsy status. The limited spectrum of possible tissue states revealed by the manifold learning is suggestive of a limited continuum along which tumor and non-tumoral cell populations can cohabitate. Such a limited low-dimensional biological space may constrain the dynamics of tumor biology in a predictable manner.
TMIC-82. LIPOCALIN-2 MEDIATES CELL-INTRINSIC AND CELL-EXTRINSIC FUNCTIONS IN GLIOBLASTOMA
Authors: Sabrina Wang, Daniel Silver, Katie Troike, Loic Deleyrolle, Justin Lathia
Journal: Neuro-Oncology (2022)

Abstract Glioblastoma (GBM) is the most common primary brain tumor with a median survival of 17-20 months. Despite therapeutic treatments including surgery, radiation, chemotherapy, a subset of GBM clones, termed cancer stem cells (CSCs) are radio-resistant and chemo-resistant, leading to mortality of the patient. CSCs also have altered metabolic profiles and have an enhanced capacity to scavenge nutrients from their microenvironment, including iron. Lipocalin-2 (LCN2) functions to sequester iron and is traditionally considered an inflammatory marker through its function of limiting iron for bacterial usage. LCN2 has been described to have both a pro and anti-tumorigenic and has context-dependent functions depending on iron status. LCN2 has been shown to be important in brain metastasis, but its role in GBM is still largely unknown. To investigate how LCN2 plays a role in the GBM microenvironment, we orthotopically implanted syngeneic mouse GBM cells into male and female LCN2 knockout and wild-type mice. Female LCN2 knockout mice succumbed to tumors faster compared to males, revealing another example of sex differences in the tumor microenvironment. To assess a cell-intrinsic function for LNC2, we added recombinant LCN2 to mouse GBM cell lines and saw that proliferation also increased. When we probed for receptor expression in our knockdown cell lines, we saw that the LCN2 canonical receptor, SLC22a17, was upregulated in response. Furthermore, in a subset of slow-cycling cells of CSCs, LCN2 was shown to be up-regulated. Taken together, these data suggest that LCN2 functions in an iron-dependent manner to affect proliferation and sex-specific tumorigenesis. Given the fact that males have more iron than females, it is worth investigating the role of iron in GBM sex difference progression and therapeutic targets.
TMIC-35. CROSSTALK BETWEEN TAMS AND GLIOBLASTOMA STEM-LIKE CELLS IN A HYPOXIC MICROENVIRONMENT INDUCES SENESCENCE ARREST AND ENHANCED RADIORESISTANCE
Authors: Tatiana Carneiro-Lobo, Cheryl Olson, Steven Markwell, Pinar Mesci, Alysson Muotri, Daniel Brat
Journal: Neuro-Oncology (2022)

Abstract Patients with glioblastoma (GBM) have an overall survival of 15 months. These catastrophic survival rates are correlated with systematic relapses that might arise from remaining glioblastoma stem cells (GSCs) left behind after treatments. Our goal was identifying whether radioresistance of GBM is caused by GSCs and how hypoxia and TAMs affect this process. First, we established a glioblastoma-brain cortical organoid (GBM-BCOs) to model human GBM. We co-cultured GFP-labeled GBM neurosphere with BCOs for 14 days and we observed that tumor take rate was 100% for all GBM neurosphere tested. Next, we evaluated whether hypoxia enhanced TAMs migration into GBM-BCOs. We incorporated THP-1 cells into GFP-GBM-BCOS for 14 days and incubated for 24 h under normoxic or hypoxic conditions. Hypoxia increased THP-1 cells influx into GBM-BCOs. Further, we investigated whether TAMs enhanced the enrichment of GSCs in GBM neurosphere and in GBM-BCOs. We found that, co-culture of THP-1 cells with GBM neurosphere or with GBM-BCOs system, enhanced CD133+ population after 72 h hypoxic condition. In addition, IF of GBM human tissue revealed increased of CD133+ and IBA1+ cells in peri-necrotic area compared to non-necrotic area and non-necrotic tumor. To examine whether TAMs enhanced the radioresistant phenotype and the quiescent population, we irradiated GBM neurosphere grown under hypoxic and normoxic conditions with different doses of γ-rays. After irradiation, these cells were co-cultured with TAMs for 72 h under normoxic and hypoxic conditions. MTT assay showed that TAMs enhanced the radioresistant phenotype promoted by hypoxia in GBM neurosphere and an increase in quiescent markers (γ-H2AX and IL-6) were found in our co-culture model after hypoxia exposure. These results indicate, not only hypoxic condition play a key role in the GSCs enrichment and radioresistance, but also crosstalk between TAMs and GSCs promote tumor oncogenesis and contribute to an ineffective anti-tumor response.